Olfactomedin 2, a novel regulator for transforming growth factor-β-induced smooth muscle differentiation of human embryonic stem cell-derived mesenchymal cells.
Bottom Line: Olfm2 also inhibited HERP1 expression.Moreover, blockade of Olfm2 expression inhibited TGF-β-induced SRF binding to SM gene promoters in a chromatin setting, whereas overexpression of Olfm2 dose dependently enhanced SRF binding.These results demonstrate that Olfm2 mediates TGF-β-induced SM gene transcription by empowering SRF binding to CArG box in SM gene promoters.
Affiliation: Department of Physiology and Pharmacology, University of Georgia, Athens, GA 30602.Show MeSH
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Mentions: Identification of Olfm2 function in SM gene transcription provides novel insights into TGF-β–induced SM differentiation. In the undifferentiated hES-MC cells or the initial phase of SM differentiation, Olfm2 is expressed at a low level, and SRF interacts with Smad3 and binds weakly to CArG box due to a substantial binding of HERP1 to SRF, resulting in a repressed state or very low level of SM marker gene transcription. When Olfm2 is induced by TGF-β via Smads and translocated into nuclei, it binds to SRF, causing SRF dissociation from HERP1, and thus removes the inhibitory effect of HERP1. Furthermore, Olfm2 facilitates and enhances SRF binding to CArG box in SM marker promoters, leading to a strong induction of SM marker expression (Figure 9). The homeostatic balance between Olfm2 and HERP1 expression appears to be an important factor in determining whether SM-specific marker genes can be effectively induced by TGF-β after the initial phase of SM differentiation.
Affiliation: Department of Physiology and Pharmacology, University of Georgia, Athens, GA 30602.